Parkinson's disease is a neurodegenerative disease which develops with high frequency with aging, and the incidence rate is more than 1% of the population aged 65 and over. It is anticipated that the number of patients with Parkinson's disease will significantly increase in association with the aging of the population in the future, and thus, it is imperative to promptly establish methods for diagnosing, preventing and/or treating Parkinson's disease.
It has been known that Parkinson's disease is developed by degeneration and/or defluxion of dopamine neurons in the substantia nigra in the midbrain. A dopamine replacement therapy involving administration of L-dopa has been carried out as the primary prognosis treatment for Parkinson's disease. However, the dopamine replacement therapy merely treats symptoms, and thus, in order to suppress the symptoms of Parkinson's disease, drug administration must be continued. Moreover, the dopamine replacement therapy has been problematic in that long-term administration of L-dopa produces progressively less effect caused by shortened duration of medicinal effects or serious side effects such as abnormal involuntary movement called “dyskinesia”. In addition, for diagnosis of Parkinson's disease, there is only a diagnostic method based on symptoms characteristic of this disease. Thus, under the current circumstances, Parkinson's disease cannot be clearly distinguished from other neurological diseases at an early stage with mild symptoms. In order to establish a radical therapy for Parkinson's disease and a method for specifically diagnosing this disease at an early stage, it is necessary to elucidate the mechanism of pathogenesis of Parkinson's disease, that is, the mechanism by which degeneration of dopamine neurons progresses. It has been desired to promptly elucidate such mechanisms.
The majority of cases of Parkinson's disease develop sporadically, but some cases are familial (hereditary) diseases. Multiple associated genes have been isolated and identified. Since sporadic Parkinson's disease shares clinical symptoms with familial Parkinson's disease, it has been assumed that the two typos of Parkinson's diseases would have a common mechanism of degeneration of dopamine cells, and thus, it has been anticipated that analysis of genes responsible for hereditary Parkinson's disease would lead to elucidation of the pathogenic mechanism of sporadic Parkinson's disease. PINK1 and Parkin have been identified as causal genes responsible for hereditary recessive early-onset Parkinsonism (Non Patent Document 1). PINK1 encodes Ser/Thr kinase localized in mitochondria, and Parkin encodes ubiquitin ligase (E3). When mitochondria lose their membrane potential, PINK1 and Parkin accumulate on mitochondria and they ubiquitinate the mitochondria, so as to induce only defective mitochondria to selective degradation (Non-Patent Document 2). An abnormality in this selective degradation mechanism of defective mitochondria (mitophagy) is considered to be a cause of neurodegeneration in Parkinson's disease.
Parkin is ubiquitin ligase (E3). E3 is the most important enzyme for determining substrate specificity in a ubiquitin-proteasome system, and in order to elucidate the pathogenic mechanism of Parkinson's disease due to abnormal mitophagy, it is extremely important to understand the mechanism of activation of Parkin. Parkin is generally present in the cytoplasm in an inactive form. When Parkin is recruited to defective mitochondria, it is activated and functions as an E3 enzyme. It has been known that PINK1 is essential for both recruitment of Parkin to mitochondria and the activation thereof (Non-Patent Document 3). Moreover, as a result of recent studies, it has been found that the autophosphorylation of PINK1 occurs with a reduction in the mitochondrial membrane potential, and thereby Parkin is phosphorylated in a PINK1-dependent manner, and as a result, Parkin is recruited to the mitochondria and is activated as an E3 enzyme (Non-Patent Document 4 and Non-Patent Document 5). However, it also has been confirmed that phosphorylation of Parkin is essential, but not sufficient, for the activation thereof. Hence, the mechanism of activation of Parkin is still only partially understood.
Parkin, which has been activated as an E3 enzyme, ubiquitinates a substrate protein on the mitochondrial outer membrane to induce the mitochondria to degrade. Ubiquitin is a protein consisting of 76 amino acids, which universally exists in all eukaryotes, and the amino acid sequence thereof is highly conserved. Studies regarding such ubiquitin have a long history, and it has been revealed that the ubiquitin acts as a tag for inducing the degradation of a substrate protein, and at the same time, it is involved in various functions such as DNA repair or intracellular signaling. Moreover, it has been studied in detail that the ubiquitin has seven lysine residues, and that the ubiquitin binds to a glycine residue at the C-terminus of another ubiquitin via these lysine residues to form a polyubiquitin chain, and various different functions are exhibited depending on the binding pattern (i.e., a difference in the shape of a polyubiquitin chain). However, it has not thus far been reported that the ubiquitin itself has undergone a certain posttranslational modification, and as a result, its function is changed.